To treat psychological and/or neurological disorders, including without limitation, attention deficit disorder, migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression, neural insult, fatigue, lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, disease related fatigue in depression and fibromyalgia, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic, and any other psychological and/or neurological syndrome it is common to prescribe to a patient a therapeutic regimen that includes an amphetamine and/or methylphenidate. An attention deficit disorder for which these therapeutics are generally prescribed is attention deficit hyperactivity disorder, also known as ADHD. ADHD is one of the most common childhood psychiatric conditions. It has been diagnosed in approximately 8.4% of all children aged 3-17 years old (Center for Disease Control and Prevention). Although scientists and clinicians debate the best way to diagnose and treat ADHD, there is no debate among competent and well-informed health care professionals that ADHD is a valid neurobiological condition that causes significant impairment to children who suffer from it.
The clinical practice parameters followed by doctors inform them that ADHD is a chronic condition that will most likely to persist into adulthood. The current standard of care recommendations state treatment should be 7 days a week, 12 months a year with no drug holidays. (see, for example, AACAP, 2007). Untreated ADHD is to known to have significant long-term consequences including loss of academic performance, social performance, and more aberrant behaviors including substance abuse, teen pregnancies and imprisonment.
Among the functional impacts of ADHD in children and adolescents are a higher risk of injury, including, without limitation bicycle/pedestrian injury, head injury and multiple injuries that require admission to an intensive care unit. Other functional impacts of ADHD include a higher rate of failure in school, higher risk of expulsion or dropout, higher rate of associated learning disability and lower rates of high school or college completion. Additionally, functional impacts of ADHD include a lack of friendships, less liked by their peers compared to non-ADHD peers, difficulty retaining peer status, a two times higher risk for tobacco smoking, a two and a half time higher risk for alcohol abuse, a two times higher risk for substance abuse, are four times more likely to contract an STD, a ten times higher risk for unplanned pregnancy, a two to six times higher rate of suspended or revoked driver's license, more traffic violations and speeding tickets, more motor vehicle accidents and greater vehicular damage. (Goodman D W, Primary Psychiatry: 17, 2 2010)
Among the function impacts of ADHD in adults are similar to those found in children and adolescents, but also include a higher likelihood of being fired or quitting a job impulsively, reduced salary, poorer work performance scores, more frequent job changes, three times more likely to be unemployed, lower occupational attainment than patient IQ would predict. Other functional impacts include a two times more likely chance to be arrested, three times more likely to be convicted, fifteen times more likely to be incarcerated, a greater tendency toward antisocial/criminal behaviour, a lower household income, higher accident claims and higher cost of accidents. (Goodman D W, Primary Psychiatry: 17, 2 2010)
Various drugs and methods have been used to treat ADHD, including amphetamine and methylphenidate based drugs. While these drugs are generally effective in treating ADHD, the side effects suffered by the children taking them can include loss of appetite resulting in weight loss, insomnia, drug dependence and loss of attentiveness.
With regard to treatments for ADHD, one option generally followed by clinicians is to prescribe the use of short-acting stimulants. These are often used as an initial treatment in small children (<16 kg), but these drugs have the disadvantage of requiring that they be administered twice a day (“b.i.d.”) or three times a day (“t.i.d.”) to provide control over a child's ADHD symptoms throughout day. Longer acting stimulants offer greater convenience, confidentiality, and compliance with single daily dosing, but the side effects suffered with these once a day drugs by children taking them is frequently more severe than the b.i.d. or t.i.d. ones.
But there are significant problems with therapeutic use of amphetamines and methylphenidates for the treatment of any neurological or psychological syndrome. For ADHD, the drugs are reported to be associated with loss of appetite in roughly 35% of patients as well as weight loss in approximately 15% of patients. In practice, it is not unusual to find that the frequency of appetite reduction and the amount of weight loss is actually greater than what has been reported in the scientific literature. (Sears clinical observation). While this effect is perceived as positive by patients who are taking amphetamines as a weight loss medication, it can be detrimental to the health and proper development of children taking medications for ADHD and other psychiatric disorders.
It is widely recognized in ADHD patients, and especially in children, that there is a documented link between patients missing meals and learning impairment. For instance, overnight and morning fasting among schoolchildren was found to have a deleterious effect on the children's memory, attention, performance in academic pursuits and ability to interact with other children socially. (Pollitt et al., 1998; Pollitt and Gorman, 1994). This correlates with the finding that regularity in breakfast consumption has been linked with improvement in academic performance and psychosocial functioning as well as cognition among children. (Benton, 2001; Bellisle, 2004).
It has been widely recognized that there is a documented link between missing meals and learning impairment for ADHD patients as well as patients suffering from a neurological or psychological syndrome. A possible reason for this link may be a drop in glucose levels resulting from missing a meal, since the supply of glucose to the brain is believed to impact upon memory, mood and attentiveness. Research suggests that when engaging in cognitively demanding tasks, such as schoolwork, repeated supplies of glucose to the brain enhances cognitive functioning and improves memory, mood and attentiveness. Research on the immediate effects of glucose on cognition demonstrated that the ability of the brain to fully function appears to be sensitive to short-term fluctuations in glucose supply. (Bellisle, 2004). Patients with nutritional deficiencies are particularly susceptible to the short-term fluctuations in glucose supply that impact upon cognitive ability, attentiveness and performance of the brain. Maintaining adequate levels of glucose throughout the day contributes to optimizing cognition and attentiveness, suggesting that nutritional intake should be designed to sustain an adequate level of glucose by minimizing fluctuations in food intake during the day.
One way to overcome issues with appetite in patients with ADHD is for the parents, spouse or other caregiver to actively monitor a patient's food intake. However, this generally only works when the patient is not resistant to eating, for instance, due to loss of appetite. Moreover, parents, spouse, or other caregiver cannot generally spend all day with a patient. This is particularly true when a majority of patients spend at least a portion of their day at school or work where they eat lunch.
Clinical guidelines for ADHD have tried to cope with appetite reduction and ADHD medication. (See for example, AACAP, 2007). Particularly, where a patient suffers deleterious effects resulting from a loss of appetite including slower growth in their height, a slowing in their weight gain and a loss in the child's attentiveness. The general standard is that if a patient has a change in height or weight that crosses two percentile lines, then this suggests an aberrant growth trajectory. In these cases the general response is for the child to stop taking the drug used to treat ADHD during weekends or during a patient's vacation or summer break if in school in order to attempt to mitigate the harm suffered by the patient. One problem with this approach is that it can lead to the marked impairment of attentiveness by a patient during the periods of time when their ADHD medication is removed. One option available to a clinician is to switch the patient to a different ADHD medication. However, as these drugs are also often either an amphetamine or a methylphenidate, it is likely that the patient will suffer from the same side effects. Knowing both the benefits and side effects of current treatment regimens, in making a treatment decision, it is incumbent upon a clinician to carefully balance the benefits of medication treatment with the risks of reductions in height and weight gain and the loss of attentiveness resulting from a lack of appetite.
Therefore it would be preferable to treat the side effects such as appetite reduction that prevent the proper use and optimal levels of amphetamine and/or methylphenidate therapy that are necessary to meet the treatment guidelines to treat ADHD or other neurological or psychological syndrome. One way to do this is through the use of appetite stimulants. These include, but are not limited to, a diverse group of medications given to patients to prevent undesired weight loss in the elderly and in patients suffering from such diseases as AIDS and cancer, diseases often associated with the wasting of the body's muscle tissue as well as overall weight loss. The medical term for these drugs is orexigenic, which is derived from the Greek word for “appetite” or “desire” and includes various drugs, including, without limitation, hormones, vitamins or other compounds known to increase appetite. This can include a naturally occurring neuropeptide hormone such as ghrelin, orexin or neuropeptide Y, or a drug or compound that increases hunger and therefore enhances food consumption.
An example of an appetite enhancement drug is cyproheptadine hydrochloride (4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride) (“cyproheptadine”). This drug has been used as oral monotherapy for allergy under the tradename Periactin®. It is known to reach peak plasma levels in 1-3 hours after administration and has a half-life of 8 hours. (Gunja, 2004). In the 1960s, it was recognized that this drug had several side effects that made it a suboptimal allergy treatment. Among the side effects were weight gain and drowsiness.
While weight gain was a side effect that made cyproheptadine a poor antihistamine, this side effect is desirable in children suffering weight loss due to loss of appetite from use of amphetamines or methylphenidates to treat ADHD. Cyproheptadine has been shown to cause weight gain in studies that used either non-human animals or humans. (Orthen-Gambill 1988). It has also been studied for its ability to promote weight gain in clinical trials for cancer cachexia. (Coulris). Other areas where there is interest in cyproheptadine to promote weight gain are tuberculosis, anorexia nervosa, cystic fibrosis, migrane, attention deficit disorder, migrane, anti-serotonergic side effects, underweight children, narcolepsy and any other psychological and/or neurological syndrome. (Coulris, Halm, Kardinal).
In ADHD, there is anecdotal evidence that a combination of an amphetamine or a methylphenidate and cyproheptadine as a treatment for children suffering from ADHD can result in weight gain and excessive sleep. (Daviss 2004). In the report, a number of children were administered their ADHD drug along with 4-8 mg of cyproheptadine at night before they went to sleep. While this report suggests that there may be a benefit of using cyproheptadine in ADHD children who are suffering weight loss as a result of taking an amphetamine or methylphenidate drug, it did not identify whether the resultant weight gain was due to the child eating over a regular eating cycle, for instance, breakfast, lunch and/or dinner or due to eating over a short period of time during which the cyproheptadine affects the child's appetite, followed by hunger during the day after the effect of the effects of the cyproheptadine have worn off. Nor did the report identify whether the administration of cyproheptadine had an effect on a child's attentiveness and ability to function cognitively and socially. Additionally, the report did not analyze the impact on height. Based on the 8 hour half-life of cyproheptadine and its administration before bed in Daviss, it is not likely that children receiving the appetite stimulant had their appetites stimulated in a manner that would result in their eating food during their waking hours. Thus, though it is not reported in Daviss, it is likely that while the children gained weight, they did not see a cyproheptadine-related improvement in attentiveness during the day, particularly, while attending school.
It is an aim of the present invention to provide a pharmaceutical composition wherein a patient suffering from a psychological and/or neurological disorder, including, without limitation, attention deficit disorder (including, without limitation ADHD), migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression (including, without limitation, augmentation of antidepressants in treating refractory depression and cancer-related depression), neural insult, fatigue (including, without limitation, disease-related fatigue in patients with HIV, advanced cancer, multiple sclerosis, myotonic dystrophy, depression, fibromyalgia and hepatitis C), lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic, and any other psychological and/or neurological syndrome is provided an amphetamine and/or a methylphenidate drug and a drug that promotes an increase in appetite. It is a further aim of the present invention to provide a pharmaceutical composition wherein a patient suffering from a psychological and/or neurological disorder, including, without limitation, attention deficit disorder (including, without limitation ADHD), migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression (including, without limitation, augmentation of antidepressants in treating refractory depression and cancer-related depression), neural insult, fatigue (including, without limitation, disease-related fatigue in patients with HIV, advanced cancer, multiple sclerosis, myotonic dystrophy, depression, fibromyalgia and hepatitis C), lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic, and any other psychological and/or neurological syndrome is provided an amphetamine and/or methylphenidate drug and a drug that promotes an increase in appetite, while maintaining or increasing the attentiveness by the patient when compared to a patient not receiving the appetite stimulant. It is an additional aim of the present invention to provide a pharmaceutical composition wherein a patient suffering from a psychological and/or neurological disorder, including, without limitation, attention deficit disorder (including, without limitation ADHD), migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression (including, without limitation, augmentation of antidepressants in treating refractory depression and cancer-related depression), neural insult, fatigue (including, without limitation, disease-related fatigue in patients with HIV, advanced cancer, multiple sclerosis, myotonic dystrophy, depression, fibromyalgia and hepatitis C), lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic and any other psychological and/or neurological syndrome is provided an amphetamine and/or methylphenidate drug and a drug that promotes an increase in appetite during the day that results in the maintenance or an increase in the attentiveness by the patient during the day when compared to a patient not receiving the appetite stimulant. It is a further aim of the present invention to provide a pharmaceutical composition wherein a patient suffering from a psychological and/or neurological disorder, including, without limitation, attention deficit disorder (including, without limitation ADHD), migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression (including, without limitation, augmentation of antidepressants in treating refractory depression and cancer-related depression), neural insult, fatigue (including, without limitation, disease-related fatigue in patients with HIV, advanced cancer, multiple sclerosis, myotonic dystrophy, depression fibromyalgia and hepatitis C), lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic, and any other psychological and/or neurological syndrome is provided an amphetamine and/or methylphenidate drug and a drug that promotes an increase in appetite during the day that results in the maintenance or an increase in the attentiveness by the patient during the day while at school, work or other situation where the patient learns, works or interacts with other people as compared to a patient not receiving the appetite stimulant. It is a further aim of the present invention to provide a pharmaceutical composition wherein a patient suffering from a psychological and/or neurological disorder, including, without limitation, attention deficit disorder (including, without limitation ADHD), migrane, anti-serotonergic side effects, narcolepsy, excessive sleepiness associated with shift work, obstructive sleep apnea as an adjunct to continuous positive airways pressure (“CPAP”), exogenous obesity, disruptive behaviour disorder including oppositional defiant disorder (“ODD”) and conduct disorder (“CD”), obesity, depression (including, without limitation, augmentation of antidepressants in treating refractory depression and cancer-related depression), neural insult, fatigue (including, without limitation, disease-related fatigue in patients with HIV, advanced cancer, multiple sclerosis, myotonic dystrophy, depression, fibromyalgia and hepatitis C), lethargy, binge eating disorder, schizophrenia, sleep cycle disorder, cocaine addiction, Parkinson's Disease, combat and non-combat related PTSD, tic, and any other psychological and/or neurological syndrome is provided an amphetamine and/or methylphenidate drug and a drug that promotes an increase in appetite during the day that results in an increase in the height of the patient taking such medication versus the same patient if such medication is not taken. By following such a therapeutic regimen, a patient will suffer fewer side effects resulting from appetite loss that can reduce treatment success and compliance, while maintaining a reasonable degree of attentiveness during the day, including, without limitation maintaining a reasonable degree of cognition and social ability.